The present invention relates to novel N-acyl and N-aroyl aralkyl amides, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1D receptors. They are useful in treating or preventing migraine, depression and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful 5-HT1A ligand therapeutics.
PCT publication WO 94121619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT1 agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT1 agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)naphthalene as a useful 5-HT1 ligand in their article xe2x80x9c5-HT1D Serotonin Receptorsxe2x80x9d, Clinical Drug Res. Dev., 22, 25-36 (1991).
Glennon""s article xe2x80x9cSerotonin Receptors: Clinical Implicationsxe2x80x9d, Neuroscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer""s disease, Parkinson""s disease and Huntngton""s disease.
World Patent Application WO 95131988, published Nov. 30, 1995, refers to the use of a 5-HT1D antagonist in combination with a 5HT1Aantagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson""s disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT1A receptors or for both 5-HT1A and 5-HT1 D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
The present invention relates to a compound of the formula 
or the pharmaceutically acceptable salt thereof, wherein
R1 is a group of the formula G1, G2, G3, G4, G5 or G6 depicted below: 
xe2x80x83wherein the broken line indicates an optional double bond;
a is zero to eight;
m is 0, 1, 2, 3 or 4;
p is 1, 2 or 3;
D is oxygen, sulfur, SO, SO2, or NR7;
E is oxygen, sulfur, SO or SO2;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, trifluoromethyl, (C1-C6)alkoxy, xe2x80x94S(O)t(C1-C6)alkyl wherein t is 0, 1 or 2, xe2x80x94CO2R10 or xe2x80x94CONR11R12.
R2 is xe2x80x94(CH2)tB, wherein t is 0, 1, 2 or 3, and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1xe2x80x94C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy-(C1C6)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, xe2x80x94COOH and xe2x80x94SOn(C1-C6)alkyl wherein n is 0, 1 or 2;
R3 and R4 are each independently hydrogen, (C1-C4)alkyl or xe2x80x94(CH2)qxe2x80x94J wherein q is 0, 1, 2 or 3, and J is phenyl or naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94S(O)k(C1-C6)alkyl wherein k is 0, 1 or 2;
R5 is hydrogen or (C1-C3)alkyl;
R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)qxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94SOg(C1-C6)alkyl, wherein g is zero, one or two;
R7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)rxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, xe2x80x94C(=O)xe2x80x94(C1-C6)alkyl, cyano and xe2x80x94SOj(C1-C6)alkyl, wherein j is zero, one or two;
or R6 and R7 taken together form a 2 to 4 carbon chain;
R8 is hydrogen or (C1-C3)alkyl;
R9 is hydrogen or (C1-C6)alkyl;
or R6 and R9, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
each of R10, R11 and R12 is selected, independently, from the radicals set forth in the definition of R3; or R11 and R12, together with the nitrogen to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; and
each R13 is, independently, (C1-C4)alkyl or a (C1-C4)methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G1 or G2, respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G1 or G2, respectively, having an available bonding site, or to a ring carbon of R6 having an available bonding site;
with the proviso that when B is hydrogen, t is not zero; and
with the proviso that when the broken line in formula G2 is a double bond, R8 is absent.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3 naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eg., potassium and sodium) and alkaline earth metal cations (e, calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention include all stereoisomers (e, cis and trans isomers) and all optical isomers of compounds of the formula I (eg., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (eg., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ca 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ringxe2x80x9d, as used herein, unless otherwise indicated, includes but is not limited to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl or benzoxazinyl.
The term xe2x80x9ca 5 to 7 membered heteroalkyl ring that may contain from one to four heteroatoms selected from nitrogen, sulfur and oxygenxe2x80x9d, as used herein, unless otherwise indicated, includes but is not limited to pyrrolidine, isoxazolidine, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidine, thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, piperazine.
Preferred compounds of the formula I include those wherein R1 is 
R6 is (C1-C6)alkyl and R3 is hydrogen.
Other preferred compounds of formula I include those wherein R2 is phenyl or benzyl optionally substituted by chloro, fluoro, bromo, iodo, (C1-C6)alkyl or trifluoromethyl. Other preferred compounds of formula I include those wherein R4 is hydrogen or (C1-C6)alkyl.
More preferred compounds of formula I include those wherein R1 is 
R6 is (C1-C6)alkyl and R3 is hydrogen; R2 is phenyl or benzyl optionally substituted by chloro, fluoro, bromo, iodo, (C1-C6)alkyl or trifluoromethyl; and R4 is hydrogen or (C1-C6)alkyl.
Specific preferred compounds of formula I include the following:
3,4-Dichloro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
4-Fluoro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-(1-methyl-2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-( 1-methyl-2-[2-(4-methylpiperazin-1-yl)-phenyl]-propyl)-benzamide;
3,4-Dichloro-N-methyl-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
N-Benzyl-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
N-(4-chlorobenzyl)-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-(2-{2-[methyl-(1-methylpyrolidin-2-ylmethyl)-amino]-phenyl}-ethyl)-benzamide;
3,4-Dichloro-N-{2-[2-(1-[methyl-octahydro-pyrrolo[2,3-c]pyridin-6yl)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-phenyl]ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(1-methylpiperidin4-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-{2-[2-(2-dimethylaminoethoxy)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2-dimethylamino-ethylsulfanyl)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2-pyrrolidin-1-ylethoxy)-phenyl]ethyl}-benzamide;
4-Chloro-N-{2-[2-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]ethyl}-benzamide;
4-Chloro-N-{2-{2-[methyl-(2-morpholin4-yl-ethyl)amino]-phenyl}ethyl)-benzamide;
2-(4-Chlorophenyl)-N-{2-[2-(4-methylpiperazin-1yl)-phenyl]-ethyl}-acetamide;
N-{2-[2-(4-Methylpiperazin-1-yl)-phenyl]-ethyl}N-phenylacetamide;
N-{2-[2-(4-Methylpiperazin-1-yl)-pheny]-ethyl)isonicotinamide;
N-{2-[2-(1-Azabicyclo[2.2.2]oct-4-yl)-phenyl]-ethyl}-N-methylbenzamide;
N-{2-[2-(1,4-Dimethylpiperidin-4-yl)-phenyl]-ethyl}-4-fluorobenzamide;
4-Fluoro-N-{2-[2-(9-methyl-3,9-diazabicyclo[3.3.1]non-3-yl)-phenyl]-ethyl}-benzamide;
N-{2-[2-(1,4-Diazabicyclo[3.3.1]non4-yl)-phenyl]-ethyl}-N-methylbenzamide;
N-{1-Methyl-2-[2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-phenyl]ethyl}-benzamide;
2,4-Dichloro-N-methyl-N-{1-methyl-2-[2-(3-methyl-3,8diazabicyclo[3.2.1]oct-8-yl)-phenyl]-ethyl}-benzamide;
N-{2-[2-(4-Methyl-octahydroquinoxalin-1-yl)-phenyl]-ethyl}-benzamide;
N-{2-[2-(1-Ethylpyrrolidin-2-ylmethoxy)phenyl]-ethyl}-benzamide;
5Phenyloxazole-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]ethyl}-amide;
5-Phenylthiophene-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;
5-Methylthiophene-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)}-amide;
4-Fluoronaphthalene-1-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-amide;
5-Fluoro-1H-indole-2-carboxylic acid {2-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-amide;
4-Chloro-N-{2-[2-(3,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide; and
3,4-Dichloro-N-{2-[2-(2,4,6trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnesic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (eg., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated in the preceding paragraph.
The present invention also relates to a method for treating or preventing a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Aizheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer, (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatc depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating or preventing a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising administering to a mammal requiring such treatment or prevention a serotonin receptor antagonizing or agonizing effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal requiring such treatment or prevention a serotonin receptor antagonizing or agonizing effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical composition for treating or preventing a condition or disorder that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising:
a) a pharmaceutically acceptable carrier;
b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and
c) a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof;
wherein the amount of the active compounds (i.e., the compound of formula I and the 5-HT re-uptake inhibitor) are such that the combination is effective in treating or preventing such disorder or condition.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal requiring such treatment or prevention:
a) a compound of the formula I defined above, or a pharmaceutically acceptable salt thereof; and
b) a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof;
wherein the amounts of the active compounds (i.e., the compound of formula I and the 5-HT re-uptake inhibitor) are such that the combination is effective in treating or preventing such disorder or condition.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising administering to said mammal requiring such treatment or prevention:
a) a 5HT1A antagonist or a pharmaceutically acceptable salt thereof, and
b) a 5HT1D antagonist of formula I or a pharmaceutically acceptable salt thereof,
wherein the amounts of each active compound (i.e., the 5-HT1A antagonist and the 5-HT1D antagonist) are such that the combination is effective in treating or preventing such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising:
a) a 5-HT1A antagonist or a pharmaceutically acceptable salt thereof, and
b) a 5-HT1D antagonist of formula I or a pharmaceutically acceptable salt thereof;
wherein the amounts of each active compound (i.e., the 5-HT1A antagonist and the 5-HT1D antagonist) are such that the combination is effective in treating or preventing such disorder or condition.
The present invention also relates to a compound of the formula 
wherein the dashed line represents an optional double bond;
R1 is a group of the formula G1, G2, G3, G4, G5 or G6 depicted below: 
xe2x80x83wherein the broken line indicates an optional double bond;
a is zero to eight;
m is 0, 1, 2, 3 or4;
p is 1, 2 or3;
D is oxygen, sulfur, SO, SO2, or NR7;
E is oxygen, sulfur, SO or SO2;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, trifluoromethyl, (C1-C6)alkoxy, xe2x80x94S(O)t(C1-C6)alkyl wherein t is 0, 1 or 2, xe2x80x94CO2R10 or xe2x80x94CONR11R12;
R4 is hydrogen, (C1-C4alkyl or xe2x80x94(CH2)qxe2x80x94J wherein q is 0, 1, 2 or 3, and J is phenyl or naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94S(O)k(C1-C6)alkyl wherein k is 0, 1 or 2;
R5 is hydrogen or (C1-C3)alkyl;
R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)qxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and xe2x80x94SOg(C1-C6)alkyl, wherein g is zero, one or two;
R7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, [(C1-C4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)rxe2x80x94, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6)alkyl, cyano and xe2x80x94SOj(C1-C6)alkyl, wherein j is zero, one or two;
or R6 and R7 taken together form a 2 to 4 carbon chain;
R8 is hydrogen or (C1-C3)alkyl;
R9 is hydrogen or (C1-C6)alkyl;
or R6 and R9, together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
each of R10, R11 and R12 is selected, independently, from the radicals set forth in the definition of R3; or R11 and R12, together with the nitrogen to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; and
each R13 is, independently, (C1-C4)alkyl or a (C1-C4)methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G1 or G2, respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G1 or G2, respectively, having an available bonding site, or to a ring carbon of R6 having an available bonding site;
R14 is amino or nitro;
with the proviso that when R14 is amino, the dashed line does not represent a double bond; and
with the proviso that when the broken line in formula G2 is a double bond, R8 is absent.
xe2x80x9cEnhanced serotonergic neurotransmission,xe2x80x9d as used herein, refers to increasing or improving the neuronal process whereby serotonin is released by a pre-synaptic cell upon excitation and crosses the synapse to stimulate or inhibit the post-synaptic cell.
xe2x80x9cChemical dependency,xe2x80x9d as used herein, means an abnormal craving or desire for, or an addiction to a drug. Such drugs are generally administered to the affected individual by any of a variety of means of administration, including oral, parenteral, nasal or by inhalation. Examples of chemical dependencies treatable by the methods of the present invention are dependencies on alcohol, nicotine, cocaine, heroin, phenolbarbitol, and benzodiazepines (e.g., Valium (trademark)). xe2x80x9cTreating a chemical dependency,xe2x80x9d as used herein, means reducing or alleviating such dependency.
Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, as used herein has the chemical formula C17H17NCI2 and the following structural formula 

Its synthesis is described in U.S. Pat. No. 4,536,518, assigned to Pfizer Inc. Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation.